The Expression and Prognostic Value of FGF2, FGFR3, and FGFBP1 in Esophageal Squamous Cell Carcinoma

Abstract

Background: Esophageal squamous cell carcinoma was treated by operation and chemoradiotherapy. However, the prognosis of most patients is poor after treatment, and most studies have shown that FGF2 and its receptor (FGFR) are involved in the development of various malignant tumors. FGF2 plays an important role in tumor progression and malignancy. In this study, the immunohistochemistry of FGF2, FGFR3, and FGFBP1 was used to further verify the expression of the three proteins in 172 patients with esophageal squamous cell carcinoma (ESCC) who had not received preoperative chemoradiotherapy and its effect on the prognosis of ESCC.

Methods: (1) χ ² test was used to analyze the relationship between proteins and clinicopathological parameters. Survival analysis was used to investigate the effect of three proteins on prognosis. (2) Paired sample t-test was used to analyze the mRNA expression of the three proteins in fresh ESCC tissues and adjacent normal tissues.

Results: FGF2 was correlated with tumor size (p = 0.026), gender (p = 0.047), and lymph metastasis (p = 0.007) in ESCC tissues. The high expression of FGFR3 was associated with tumor differentiation (p = 0.043 and p < 0.05), lymph node metastasis (p = 0.078 and p < 0.1), and race (p = 0.033 and p < 0.05). The high expression of FGFBP1 was significantly associated with the degree of tumor differentiation (p = 0.012), age (p = 0.045), and lymph node metastasis (p = 0.032) of ESCC patients. The expression of FGF2, FGFR3, and FGFBP1-mRNA in ESCC tissues was significantly higher than that in adjacent tissues (p < 0.001, p < 0.001, and p = 0.001). Patients with high expression of FGF2, FGFBP1, and FGFR3 had poor prognosis. There was a weak positive correlation between FGF2 and FGFBP1, as well as FGFR.

Conclusion: The FGF2-FGFR3 axis may promote the progression of esophageal squamous cell carcinoma. The FGF2-FGFR3 axis may be a new direction of targeted therapy for esophageal squamous cell carcinoma. FGF2 and FGFR3 may be used as prognostic markers of esophageal squamous cell carcinoma.

Figure 1

Immunohistochemical staining of FGF2, FGFR3, FGFBP1 expression in ESCC and normal esophagus mucosa. (a, b) Positive expression of FGF2 in ESCC tumor tissue; (c) positive expression of FGF2 in the basal layer of normal esophageal mucosa; (d, e) positive expression of FGFR3 in ESCC tumor tissue; (f) positive expression of FGFR3 in the basal layer of normal esophageal mucosa; (g, h) positive expression of FGFBP1 in ESCC tumor tissue; (i) negative expression of FGFBP1 in normal esophageal mucosa.

Figure 2

The expression of FGF2, FGFR3, and FGFBP1-mRNA in cancer tissues was significantly higher than that in adjacent tissues (p < 0.05).

Figure 3

Kaplan–Meier curves for overall survival of ESCC with lymph node metastasis, vascular invasion, nerve invasion, and the treatment of surgery plus chemotherapy. (a) Patients with vascular invasion have a significantly shorter survival (p = 0.011); (b) patients with lymph node metastasis have a significantly shorter survival (p = 0.006); (c) patients with nerve invasion have a significantly shorter survival (p = 0.02); (d) patients who had postoperative chemoradiotherapy have a significantly longer survival (p = 0.002).

Figure 4

Kaplan–Meier curves for overall survival of ESCC with FGF2, FGFR3, and FGFBP1 expression. (a) Patients expressing high level of FGF2 have a significantly shorter survival (p < 0.001); (b) patients expressing high level of FGFR3 have a significantly shorter survival (p < 0.001); (c) patients expressing high level of FGFBP1 have a significantly shorter survival (p < 0.001).

Figure 5

Kaplan–Meier curves for PFS of ESCC. (a) Patients with lymph node metastasis have a significantly shorter survival (p = 0.005); (b) patients with vascular invasion have a significantly shorter survival (p = 0.008); (c) the prognosis of patients with distant metastasis is poor (p = 0.008); (d) patients expressing high level of FGF2 have a significantly shorter survival (p < 0.001); (e) patients expressing high level of FGFR3 have a significantly shorter survival (p < 0.001); (f) patients expressing high level of FGFBP1 have a significantly shorter survival (p < 0.001).

Figure 6

Kaplan–Meier survival analysis: total and progression-free survival in patients undergoing postoperative chemotherapy. (a) The OS of patients with FGF2 overexpression was shorter in ESCC (p = 0.025); (b) the high expression of FGFR3 had a poor OS in ESCC (p = 0.05); (c) the high expression of FGFBP1 had a poor OS in ESCC (p = 0.005); (c) the PFS of patients with FGF2 overexpression was shorter in ESCC (p < 0.001); (e) the high expression of FGFR3 had a poor PFS in ESCC (p < 0.001); (f) the high expression of FGFBP1 had a poor PFS in ESCC (p < 0.001).

Figure 7

The connection diagram of FGF2, FGFR3, and FGFBP1.